Potent synergistic effect of natural product-inspired Sinomenine derivatives with fluconazole against azole-resistant Candida albicans.

Candida albicans (C. albicans) is the most common cause of invasive Candida infections worldwide. The acquired resistance of C. albicans to fluconazole, a first-line antifungal drug, has been frequently reported, posing significant challenges to treatment. Combination therapy has emerged as an effective strategy to combat drug resistance. In this study, we synthesized a series of sinomenine derivatives and evaluated in vitro synergistic activity against azole-resistant C. albicans. The results demonstrated that compound 3ja exhibited a potent synergistic effect with fluconazole against azole-resistant C. albicans. Mechanism studies revealed that the combination of 3ja and FLC significantly induced reactive oxygen species accumulation, disrupted membrane integrity, altered membrane sterols, and promoted apoptosis in C. albicans.